System, method and catheter for pituitary and brain implantation

ABSTRACT

The present invention relates to a system, its catheter and its method for providing electrical pulses and/or therapeutic or diagnostic liquids directly to a pituitary gland of a mammal. The catheter, containing an electrode or a microcannula or both, is moved through an endovascular route of a patient to his/her sinus cavernosus and then the distal end of the electrode or microcannula is moved through an opening in the distal end of the catheter and then through a perforation in the medial wall of the sinus cavernosus, to the pituitary gland.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional under 35 U.S.C. § 121 of co-pendingU.S. application Ser. No. 16/764,127 filed May 14, 2020, which is a 35U.S.C. § 371 National Phase Entry Application of InternationalApplication No. PCT/NL2018/050765 filed Nov. 14, 2018, which claimsbenefit under 35 U.S.C. § 119(b) of NL Application No. 2019909 filedNov. 14, 2017, the contents of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to a system for endovascular implantationof a catheter within a mammal body. The present invention particularlyrelates to a system for endovascular implantation of a cathetersupplying electrical energy or therapeutic or diagnostic fluids ormaterials, such as stem cells, particularly to the pituitary gland,pituitary stalk, basal ganglia and/or hypothalamus of the brain.

BACKGROUND OF THE INVENTION

It is known to implant a catheter, containing an electrode coupled to asource of electrical pulses, directly in a patient's brain, through thecerebral cortex, to modify their activity by deep brain stimulation.This can give relief to the symptoms of, for example, Parkinson'sdisease, depression and compulsive disorders. The catheter can alsocontain a tube for injecting a therapeutic or diagnostic liquid directlyin the brain or neurological tissue to modify their activity, see forinstance U.S. Pat. No. 7,505,807B1 and U.S. Pat. No. 8,116,883B2.

Similarly, hormonal activity of glands, such as the pituitary, thymusand adrenal glands can be modified, using such a catheter to provideelectrical pulses and/or therapeutic or diagnostic liquids directly tothe glands, see for instance U.S. Pat. No. 8,515,542B2 andUS2008065002A1.

However, it has been a particularly difficult problem to provideelectrical pulses and/or therapeutic or diagnostic liquids with acatheter directly to the pituitary gland, or to the pituitary stalk andhypothalamus via the pituitary gland. This is because the catheter hashad to be inserted in the pituitary gland through the sphenoid sinus(the airy nasal cavity that is located before/under the sella) of thepatients. The pituitary gland, which is in the sella, is separated fromthe sphenoid sinus by a layer of the dura mater (hard brain membrane),bone and mucous membrane of the nasal cavity.

Providing electrical pulses and/or therapeutic or diagnostic liquids tothe pituitary gland through the sphenoid sinus has therefore beendifficult because the catheter has had to be inserted through the hardbrain membrane, bone and mucous membrane of the nasal cavity. Also, thecatheter has had to be inserted through the patient's nose which hasposed a significant infection risk to the patient, as described forinstance in U.S. Pat. No. 5,735,817 A.

Furthermore, the catheter has had to be connected to a regulatingdevice, which is approachable for maintenance and adjustment. Therefore,the catheter has had to be guided outside the nasal cavity to a suitableplace for connection. A catheter coming out a person's nostril has beenunappealing and has had a risk of easy dislocation. Therefore, thecatheter has had to again be placed through mucous membrane and bone toenter a subcutaneous space in the face, from which it can be guided tothe stimulating device.

Because of the importance of the pituitary gland (which is the centralhormone gland of the brain through which essential body functions, suchas menstrual cycle, stress response, and paediatric growth areregulated), an alternative system has been sought for providingelectrical pulses and/or therapeutic or diagnostic liquids and materialswith a catheter directly to the pituitary gland and from there to thepituitary stalk (which is the connection between the hypothalamus andthe pituitary) and the hypothalamus (which is a portion of the brainthat links the nervous system to the endocrine system via the pituitarygland).

SUMMARY OF THE INVENTION

This invention relates to a system for providing electrical pulsesand/or therapeutic or diagnostic liquids directly or indirectly to apituitary gland of a mammalian patient or to a pituitary stalk or to ahypothalamus of the mammalian patient via the pituitary gland, using acatheter that has a distal end movable distally through blood vessels,in an endovascular route, of the mammal and then into and through asinus cavernosus of the mammal and that contains an action member, adistal end of which is movable distally within an elongated hollow tubeof the catheter, the system being characterized by comprising, as anaction member, an electrode and/or a microcannula having a distal endthat can move:

-   -   distally, within the hollow tube of the catheter, through the        endovascular route and then into and through the sinus        cavernosus; and then    -   distally out of the catheter through an opening in the distal        end of the catheter and then through a perforation in a medial        wall of the sinus cavernosus to the pituitary gland and then to        and into or under or around the pituitary gland;    -   wherein the system is capable of actively bending the hollow        tube of the catheter to a predetermined angle of no less than        750 when moving along the endovascular route. Advantageously,        the angle is at least 80°, more advantageously at least 85°, yet        more advantageously at least 90°.

Advantageously, the system is operable to move the distal end of theaction member, within the hollow tube of the catheter, via theendovascular route from a vena jugularis of the mammal, to an inferioror superior petrosal sinus of the mammalian patient, and then to thesinus cavernosus of the mammalian patient. More advantageously, thedistal end of the catheter moves via the endovascular route from theileac vein or femoral vein in a groin or the cephalic vein in the arm ofthe mammalian patient where the catheter is inserted in the mammalianpatient.

Also advantageously, the catheter of the system comprises an exteriorlumen within the hollow tube of the catheter and an interior lumenwithin the exterior lumen, the exterior lumen containing a firststeering mechanism and the interior lumen containing a second steeringmechanism, and the first and second steering mechanisms being operableto actively bend the hollow tube to a predetermined angle of no lessthan 75°.

Also advantageously, the catheter of the system has an action membercomprising a push wire having a distal end that can move:

-   -   distally, within the hollow tube of the catheter, through the        endovascular route and then into and through the sinus        cavernosus; and then;    -   distally out of the catheter through the opening in the distal        end of the catheter and then through the perforation in the        medial wall of the sinus cavernosus.        More advantageously, the distal end of the push wire comprises a        tip containing a sharp, advantageously pointed, element that can        be projected distally from the opening in the distal end of the        catheter to form the perforation in the medial wall of the        cavernous sinus.

Also advantageously, a distal-most part of the catheter of the systemincludes a malleable cushion to allow good contact of the distal-mostpart with the surface of the medial wall of the sinus cavernosus. Alsoadvantageously, the exterior of a distal part of the catheter,advantageously between the collar and the cushion, has a radiopaque ringthat can be recognized, and made visible, by an imaging device, such asan X-ray, fluoroscopy, angiogram, MRI or a CT-scan device to facilitateproper positioning of the distal part of the catheter in the patient.(This visibility or recognition ability is further referred to herein as“radiopacity”). Additionally or alternatively, a distal part of thecatheter, advantageously between the collar and the cushion, containsone or more electromagnetic localizers to facilitate proper positioningof the distal part in the patient. Each localizer is part of a trackingsystem, in which the localizer includes a transmitter and receiver coilarray, enabling it to transmit electromagnetic signals and receiveelectromagnetic energy from a transmitter coil array. The transmittercoil can suitably be located in, or adjacent to, the patient and cangenerate an electromagnetic field to energize each localizer.

Also advantageously, the exterior of the distal end of the catheter ofthe system, adjacent to, and proximal of, the cushion, has an annularcollar that can be inflated, so that distal surfaces of the collar areprojected distally from the distal end of the catheter around theperforation in the medial wall of the cavernous sinus to close a spacearound the opening in the distal end of the catheter between the distalend of the catheter and the perforation, advantageously before the tipof the push wire is projected distally from the opening in the distalend of the catheter to form the perforation in the medial wall of thecavernous sinus. More advantageously, the exterior of the distal end ofthe catheter, adjacent to, and proximal of, the inflatable annularcollar, also has a stabilizing device, to secure the position of thedistal end of the catheter within the perforation in the medial wall ofthe sinus cavernosus, without occluding the perforation, the stabilizingdevice comprising an inflatable tripod, provided circumferentially aboutthe exterior of the catheter and having inflatable, radially extendablelegs.

Also advantageously, the catheter of the system comprises a thirdsteering mechanism comprises guide wire within the hollow tube forpivoting or steering the distal end of the catheter in a desireddirection, advantageously by remote control, for controlling its distalmovement through the endovascular route and then into and through thesinus cavernosus.

Also advantageously: the catheter of the system has an action membercomprising an electrode, the distal end of which has one or more contactpoints for electrical stimulation of endocrine tissue of the pituitarygland, the pituitary stalk or the hypothalamus; and/or the one or moreaction members comprise a microcannula, the distal end of which has oneor more central or wall-located hollow channels, each with one or moreside openings, through which small volumes of a fluid or gel can flowinto the pituitary gland, the pituitary stalk or the hypothalamus, stillmore advantageously with side openings that can be opened and closed byremote control. Advantageously, the electrode comprises one or morepenetrating electrodes, one or more surface area electrodes, or acombination of both. More advantageously, the electrode design andelectrode placement is such that a focal electrical field is generated.

The electrode is advantageously adapted to: electrically stimulate thepituitary gland to produce and secrete adrenocorticotropic hormone(ACTH) and/or alpha-melanocyte stimulating hormone (MSH) and/oroxytocin; and/or electrically stimulate the pituitary gland to stimulatethe magnocellular nuclei of the anterior hypothalamus through axons thatdescend through the pituitary stalk to the pituitary gland. Also moreadvantageously, distal portions of the electrode or microcannula or bothhave a form memory and thus can form a three-dimensional shape, such asa circle, oval or helix, within or about the pituitary gland,advantageously when triggered by remote control. Still moreadvantageously, distal portions of the electrode, when inserted in thepituitary gland, have a coil shape within the pituitary gland.

Also advantageously, the catheter of the system, particularly its hollowtube, has a peel-away configuration, so that an electrode ormicrocannula can subsequently be removed from the patient through thecatheter in such a way, that the electrode or microcannula remainsintact.

This invention also relates a catheter, advantageously the catheter ofthe system of the invention, for providing electrical pulses and/ortherapeutic or diagnostic liquids directly to a pituitary gland of amammal or to a pituitary stalk or to a hypothalamus of the mammal viathe pituitary gland, a distal end of the catheter containing one or moreaction members, a distal end of each of which can move distally in thecatheter via blood vessels of an endovascular route of the mammal andthen via a sinus cavernosus of the mammal to a medial wall of thecavernous sinus; the catheter being characterized by: the one or moreaction members comprising a push wire having a distal end having a tipwith a sharp, advantageously pointed, element that can be projecteddistally from an opening in the distal end of the catheter to form aperforation in the medial wall of the cavernous sinus, through which: adistal end of another action member, advantageously an electrode or amicrocannula or both can be moved distally through the cavernous sinusand the electrode and/or microcannula can then be inserted in, orunder/around the pituitary gland from the distal end of the catheter.

This invention further relates to a method for providing electricalpulses and/or therapeutic or diagnostic liquids directly to a pituitarygland of a mammal or to a pituitary stalk or to a hypothalamus of themammal via the pituitary gland, comprising the steps of:

-   -   moving a distal end of a catheter, advantageously the catheter        of the system of this invention, that contains one or more        action members, a distal end of each of which is movable        distally within the catheter, through an endovascular route of        the mammal from a vena jugularis of the mammal, to an inferior        or superior petrosal sinus of the mammal, and then to a sinus        cavernosus of the mammal; and then    -   perforating a medial wall of the cavernous sinus to the        pituitary gland; and then    -   moving the distal end of the one or more action members distally        from the catheter, through an opening in the distal end of the        catheter and through the perforated medial wall of the sinus        cavernosus, to the pituitary gland.        Advantageously, the distal end of each of the one or more action        members moves via the endovascular route from the ileac vein or        femoral vein in a groin or the cephalic vein in the arm of the        mammal where the catheter is inserted in the mammal.

This invention yet further relates to a method of treatingendocrinological medical conditions related to the components of theendocrine system such as the adrenal glands, pituitary gland, andhypothalamus with the system and the catheter of this invention.Non-limiting examples of such endocrinological conditions includehypoglycemia, diabetes type I and II, obesity, hyperthyroidism,hypothyroidism, amenorrhea, dysmenorrhea, infertility, impotence,anorgasmia, delayed orgasm, perimenstrual syndrome,hypercholesterolemia, hypertriglycridinemia, Cushing's disease,Addison's disease, Addison's crisis, malabsorption syndrome,dysautonomia, chronic fatigue syndrome, fatigue, heat exhaustion, coldextremities, hot flashes, vasomotor instability, Raynaud's syndrome,hormonal disorders, metabolic disorders such as gout, disorders ofmetabolism and metabolic storage diseases where there is an accumulationof abnormal amounts of various substances such as glycogen in glycogenstorage diseases, iron in hemochromatosis or copper in Wilson's disease,auto-immune disorders, sleep disorders and disruptions in the circadianrhythm. In particular, the invention relates to the treatment ofAdison's disease and Adison's crisis.

Typical treatment for Adison's disease involves replacing the absenthormones by administration of a corticosteroid such as hydrocortisoneand fludrocortisone, which needs to be applied in relatively largeamounts, and potentially requiring a lifelong, continuous steroidreplacement therapy, with regular follow-up treatment and monitoring forother health problems. In the case of a crisis, an injection ofcorticosteroid is usually required. Without treatment, an adrenal crisiscan result in death.

However, the treatment method of this invention now permits triggeringof the patient's own production of steroid hormones by triggering thefeedback loop in the patient's own pituitary gland, or even thepatient's hypothalamus, e.g., by in situ administration of CRH or auseful analogue thereof, or a combination of CRH with otherpharmacologically active components like vasopressin, or focalelectrical stimulation.

This invention still further relates to a method of treating, with thesystem and the catheter of this invention, pain, pain perception,post-traumatic stress disorder, epilepsy, depression, anxiety disorders,and other similar conditions through stimulation of the posterior lobeof the pituitary gland, the intermediate lobe, the anterior lobe of thepituitary gland, or a combination of these.

BRIEF DESCRIPTION OF THE DRAWINGS

The following exemplary drawings illustrate preferred embodiments of theinvention. Other objects and features will be apparent from thefollowing description and drawings in which the following figuresdisclose as follows:

FIG. 1 A schematic illustration of a preferred embodiment of thisinvention: flexible catheter 1 containing a flexible guide wire 2 andhaving an opening at its distal end, through which the guide wireextends distally.

FIG. 2 The catheter of FIG. 1 , showing, within it: i) an action member5, e.g., an electrode or a microcannula, with its distal end incommunication with the opening in the distal end of the catheter and ii)a guide wire steering system 6 with its proximal end connected to theproximal end of the catheter.

FIG. 3 The catheter of FIG. 1 , showing, within it: i) its action member5 and ii) its steering system 6 with its distal end connected to thedistal end of the catheter; and showing on its distal end: i) its collardeflated 10, ii) its malleable cushion 8 with an annular radiopaque andelectro-stimulating ring 7 about it, and iii) its elastic, stretchableand radiopaque annular cuff 9 around a distally-extending centralopening that is in communication with the opening in the distal end ofthe catheter, through distally-extending central openings (not shown) inthe collar 10 and cushion 8.

FIG. 4 The catheter of FIG. 3 , showing its distal end moved adjacentthe medial wall of the sinus cavernosus with: i) its collar 10 deflatedand ii) its cushion 8 in contact with the medial wall 11 of the sinuscavernosus.

FIGS. 5 and 6 he catheter of FIG. 4 , showing: i) its collar 10 distallysubsequently inflated against the medial wall 11 of the sinus cavernosusand ii) its cushion 8 then moved proximally towards the medial wall 11of the sinus cavernosus.

FIG. 7 The catheter of FIGS. 5 and 6 , showing: i)) its collar 10distally inflated against the medial wall 11 of the sinus cavernosus andii) its cushion 8 subsequently moved distally against the medial wall ofthe sinus cavernosus by applying suction to the proximal end of thecatheter to suck venous blood out of the space 12 between the distal endof the catheter and the medial wall 11 of the sinus cavernosus throughthe central openings in the collar 10, cushion 8 and elastic cuff 9 ofthe catheter.

FIG. 8 The catheter of FIG. 3 , showing a push wire 13 extendingdistally through the catheter and through the central openings in itscollar, cushion and cuff and with a sharp, perforating tip at the distalend of the push wire; the tip extends distally out of the catheterthrough the central opening in the cuff, so that the tip can perforatethe medial wall of the sinus cavernosus; the diameter of the push wireis smaller than the guide wire 2.

FIG. 9 The push wire of FIG. 8 , showing its sharp, perforating tip atits distal end.

FIG. 10 The catheter of FIG. 7 showing: i) its cushion in contact withthe medial wall of the sinus cavernosus and ii) an endovascular actionmember 15 extending outwardly of the distal end of the catheter andthrough the central openings in its collar, cushion and cuff and thenthrough a perforation in the medial wall of the sinus cavernosus to thepituitary gland. for subdural treatment thereof.

FIG. 11 The catheter of FIG. 10 , showing: i) its cushion moved awayfrom the medial wall of the sinus cavernosus and ii) the endovascularaction member 15 extending distally through the catheter and its collar,cushion and cuff and outwardly of the opening in the distal end of thecatheter and through the central openings in its collar, cushion andcuff and then through a perforation in the medial wall 11 of the sinuscavernosus to the pituitary gland 16 for subdural treatment thereof.

FIG. 12 The catheter of FIG. 11 , showing an anchoring foam 17, used toseal the opening in the medial wall 11 of the sinus cavernosus aroundthe endovascular action member 15 extending outwardly of the opening inthe distal end of the catheter and through the central openings in itscollar, cushion and cuff and then through the opening in the medial wallof the sinus cavernosus to the pituitary gland.

FIG. 13 The catheter of FIG. 12 , showing the anchoring foam 17, used toseal the opening in the medial wall 11 of the sinus cavernosus around asecond guiding catheter 18, releasing a further action member 15extending upwardly of the opening in the distal end of the secondcatheter through the pituitary gland 16 into the pituitary stalk 19.

FIG. 14 The path of the distal end of an endovascular electrode 24, asan action member, that has been moved within the catheter of FIGS. 1 to12 via the vena jugularis and then via the inferior or superior petrosalsinus to the sinus cavernosus.

FIG. 15 The path of the distal end of the endovascular electrode 24 ofFIG. 14 that has then been moved distally, from the distal end of thecatheter, then moved through a perforation in the medial wall of thesinus cavernosus and then been inserted into the pituitary gland 16.

FIG. 16 The path of the distal end of the endovascular electrode 24 ofFIG. 15 that has then been moved through the pituitary gland 16, thensteered vertically and then inserted into, or parallel to, the pituitarystalk.

FIG. 17 The path of the distal end of the endovascular electrode 24 ofFIG. 16 that has then been steered further vertically, then passedthrough, or parallel to, the pituitary stalk and then being insertedinto the core of the hypothalamus.

FIG. 18 The path of the distal end of the endovascular electrode 24 ofFIG. 15 that has then formed a coil inside the pituitary gland 16.

FIG. 19 A stabilizing device 28 on the exterior of the distal end of thecatheter of FIG. 8 to secure the position of the distal end of thecatheter within the perforation in the medial wall of the sinuscavernosus, without occluding the perforation.

FIG. 20 The catheter of FIG. 19 showing: the endovascular electrode 24of FIG. 14 then moving distally, from the distal end of the catheter,then moving through the medial wall of the sinus cavernosus and thenextending through an opening in the medial wall of the sinus cavernosusto either just beneath the pituitary gland for subdural treatmentthereof or inserted in the surface of the pituitary gland for epiduraltreatment thereof.

DETAILED DESCRIPTION OF THE INVENTION

Herein, the term “an action member” preferably means one or moreelectrodes or one or more microcannulas or one or more push wires or anyor some or all of them within a catheter.

Also herein, the term “guide wire” preferably means a tiny elongatedwire designed to navigate a vessel to reach a segment of the vessel.Once the tip of the wire arrives at its destination, it acts as a guidethat a larger catheter can rapidly follow for easier delivery to thedestination. Such wires are characterized by their pushability,steerability, torque and opacity.

Pushability is the amount of force needed to advance the wire.Steerability is the ability and responsiveness of the wire tip tonavigate vessels. Torque is the response of the wire to turning by theoperator when navigating vessels. Opacity is its level of visibilityunder fluoroscopic imaging.

Also herein, the term “catheter” preferably means an elongated hollowflexible tube, made from a medical grade material, for insertion into avessel. The tube makes it easier to enter the vessel and move within itwith other devices or instruments, such as lasers, stents, and balloonsfor angioplasty.

Also herein, the term “microcannula” preferably means an elongated thintube, the distal end of which can penetrate one or more cells of amammalian patient. A microcannula with a capillary tube has a bore thinenough to deliver a minute drop of a liquid to a single cell penetratedby the microcannula and thereby treat, e.g., stimulate, the single cellor multiple cells by allowing injected fluid to diffuse among the cells.A microcannula which is not a capillary tube can be used to hold amovable push wire and/or provide air pressure for inflation/deflation,an anchoring foam, and/or other elements to manipulate elements at thedistal end of the catheter. Each microcannula can be extended throughthe elongated hollow tube of the catheter and subsequently retractedfrom the catheter through its elongated hollow tube.

Also herein, the term “distal end” preferably means the portions of acatheter or any of its action members at their distal extremities andtheir parts adjacent their distal extremities.

Also herein, the terms “mammalian patient” and “mammal” are usedinterchangeably and preferably mean a human or mammalian animal, such asa dog, particularly a human, in need of treatment.

Also herein, the term “femoral vein” preferably includes the inferiormargin of the inguinal ligament which is known as the external iliacvein and is below the inguinal ligament.

Also herein, the term “endocrinological medical condition” preferablymeans a problem related to the components of the endocrine system, suchas the adrenal glands, pituitary gland, and hypothalamus, includinghypoglycemia, diabetes type I and II, obesity, hyperthyroidism,hypothyroidism, amenorrhea, dysmenorrhea, infertility, impotence,anorgasmia, delayed orgasm, perimenstrual syndrome,hypercholesterolemia, hypertriglycridinemia, Cushing's disease,Addison's disease, Addison's crisis, malabsorption syndrome,dysautonomia, chronic fatigue syndrome, fatigue, heat exhaustion, coldextremities, hot flashes, vasomotor instability, Raynaud's syndrome,hormonal disorders, metabolic disorders such as gout, disorders ofmetabolism and metabolic storage diseases where there is an accumulationof abnormal amounts of various substances such as glycogen in glycogenstorage diseases, iron in hemochromatosis or copper in Wilson's disease,auto-immune disorders, sleep disorders and disruptions in the circadianrhythm. In particular the present invention relates to the treatment ofAdison's disease and Adison's crisis, as well as pain, pain perception,post-traumatic stress disorder, depression and anxiety.

The system of this invention, as shown in FIGS. 1-12 , provideselectrical pulses and/or therapeutic or diagnostic liquids to apituitary gland of a mammalian patient or to a pituitary stalk or to ahypothalamus of the mammalian patient directly or indirectly (i.e.,subdurally) as shown in FIGS. 10 and 11 or indirectly (epidurally),i.e., about or adjacent or beneath or above the pituitary gland,pituitary stalk or the hypothalamus as shown in FIG. 20 . The systemuses a catheter 1 that has a distal end movable distally through one ormore blood vessels of an endovascular route of the mammal. Through thecatheter, one or more action members 5 or 15, preferably one or moreelectrodes 5 or 15 or one or more microcannulas 5 or 15 or one or morepush wires 13 or any or some or all of them may be inserted, a distalend of each of which is movable distally within the catheter 1 and, viathe catheter, through the endovascular route and then into and throughthe sinus cavernosus of the mammal.

The system preferably comprises an electrode array is provided forinterfacing with the organ tissue in situ, the device comprising: a. adeformable array of electrodes comprising a plurality of electrodes inelectrical communication with a plurality of deformable electricalinterconnects and a connector line; wherein the deformable array ofelectrodes provides a net bending stiffness of the array low enough thatthe device is capable of establishing conformal contact with the tissuein situ; and b. a connection plug provided at the proximal end of theconnector line of the electrode array provided with a distal end ofwhich can be attached to a bone adjacent the organ, such an anteriorwall of the sphenoid sinus/vomer, and a proximal end of which can bereversibly connected electrically to a wire that is connectedelectrically to a source of electrical stimulation for the organ.

The catheter 1 of the system shown in FIGS. 1-12 contains one or moremicrocannula or electrodes 5 or 15, as action members, extending throughits elongated hollow tube. At least one of the action members has adistal end that can move:

-   -   distally within the catheter, through the endovascular route and        then into and through the sinus cavernosus; and then    -   distally out of the catheter, through an opening in the distal        end of the catheter and then through a perforation in the medial        wall of the sinus cavernosus to the pituitary gland and then to        and into the pituitary gland, preferably when the distal end of        the catheter is adjacent the medial wall of the sinus        cavernosus.

The catheter 1 of the system shown in FIGS. 1-12 can also contain, inits elongated hollow tube, one or more additional microcannula 5 or 15,through which can be provided a movable push wire 13 and/or air pressurefor inflation/deflation (e.g., of the collar 10 or a stabilizing device28), an anchoring foam 17, and/or other elements to manipulate elementsat the distal end of the catheter, such as the collar 10 or the ring 7.Alternatively, the push wire 13, air pressure for inflation/deflation,an anchoring foam, or other elements to manipulate elements at thedistal end of the catheter can be provided directly through theelongated hollow tube of the catheter, Preferably, the push wire 13 hasa distal end that can move:

-   -   distally, within an additional microcannula 5 or 15 in the        catheter, through the endovascular route and then into and        through the sinus cavernosus; and then    -   distally out of the additional microcannula and the catheter        through an opening in the distal end of the catheter and then        through the perforation in the medial wall of the sinus        cavernosus.        The distal end of the push wire 13 preferably has a tip 14 with        a sharp, preferably pointed, distal element 14 that can be        projected distally, through the opening in the distal end of the        catheter, to perforate the medial wall of the sinus cavernous.        Also preferably, the tip of the catheter has one or more        conventional sensors or a Doppler probe to allow identification        of cranial nerves or arteries.

Preferably, the elongated hollow tube of the catheter 1 of the systemalso contains a flexible guide wire 2, preferably with a blunt andatraumatic distal end, to guide the catheter through the endovascularroute and and then into and through the sinus cavernosus. The distal endof the guide wire can be provided with a Doppler probe to identify thecarotid artery and/or with an electrical stimulation device foridentification of the abducens nerve.

Preferably, one or more action members of the catheter 1 of the systemare located within the elongated hollow tube of the catheter. Aconventional catheter 1 containing one or more conventional microcannula5 or 15 can be used in this system. Each microcannula can: i) contain anelectric wire for carrying a pulsed current to an electrode 5 or 15 (notshown) at the distal end of the catheter for providing electricalstimulation, at the distal end of the catheter or ii) carry a diagnosticor therapeutic liquid to the distal end of the catheter. Preferably, themicrocannula for carrying a diagnostic or therapeutic liquid is amicrocannula with a capillary tube. Also preferably, the distal end ofeach electrode has one or more contact points for electrical stimulationof endocrine tissue of the pituitary gland, the pituitary stalk or thehypothalamus. Also preferably, the distal end of each microcannula for aliquid has one or more side openings which are in communication with themicrocannula's central hollow channel and through which:

-   -   small volumes of a fluid or gel can flow from a microcannula        into the pituitary gland, the pituitary stalk or the        hypothalamus, still more preferably with side openings that can        be opened and closed by remote control; and/or    -   small volumes of a pressurized gas can flow from a microcannula        into the collar 10 to inflate it, so that distal surfaces of the        collar are projected distally from the distal end of the        catheter around a perforation in the medial wall of the        cavernous sinus to close a space around the opening in the        distal end of the catheter between the distal end of the        catheter and the perforation, preferably before the tip of the        push wire is projected distally from the opening in the distal        end of the catheter to form the perforation in the medial wall        of the cavernous sinus.

Also preferably, an annular radiopaque collar or ring 7 is provided on adistal part of the exterior of the tubular wall of the catheter 1 of thesystem, spaced away from the distal end of the catheter. The ring 7allows the position of the distal part of the catheter to be identifiedwith X-ray, MRI or CT-scan.

Also preferably, the distal end of the tubular wall of the catheter 1 ofthe system holds a cushion 8 that allows the distal end of the catheterto have good, preferably liquid tight, contact with the surface of themedial wall of the sinus cavernosus and thereby prevent venous bloodfrom the cavernous sinus leaking into the sella or in or around thepituitary gland. The exterior of the distal end of the catheter,adjacent to, and proximal of, the cushion 8, is preferably provided withthe radiopaque ring 7. Within the cushion 8 is preferably a centralstretchable, elastic cuff 9, which at rest closes the opening in thedistal end of the catheter 1, but can be stretched to allow movement,through its full diameter, of the push wire, 13 and/or subsequently asealing plug or the anchoring foam 17. In this regard, the sharp tip 14of the push wire 13 can be projected distally from the distal end of thecatheter, through the opening, in the cushion 8 to perforate the medialwall of the cavernous sinus, and subsequently to force the anchoringfoam distally from the catheter into the perforation made by the sharpelement to close the perforation.

Also preferably, the exterior of a distal part of the catheter 1 of thesystem, adjacent to, and proximal of, the ring 7, is provided with aninflatable collar 10, which is flush with the outer surface of thetubular wall of the catheter when deflated. The ring 7 is preferablybetween the collar 10 and the cushion 8.

Also preferably, a distal part of the catheter 1 of the system,preferably between the collar 10 and the cushion 8, contains one or moreelectromagnetic localizers (not shown) to facilitate proper positioningof the distal part in the patient. Each localizer is part of a trackingsystem, in which the localizer includes a transmitter and receiver coilarray, enabling it to transmit electromagnetic signals and receiveelectromagnetic energy from a transmitter coil array. The transmittercoil can suitably be located in, or adjacent to, the patient and cangenerate an electromagnetic field to energize each localizer. Suitablelocalizers and tracking systems include, for instance, those describedin U.S. Pat. No. 8,549,732 B2 and U.S. Pat. No. 9,717,442 B2.

Also preferably, the catheter 1 of the system includes an integratedsteering system, such as a guide wire within the elongated hollow tubeof the catheter for pivoting or steering the distal end of the catheter,preferably by remote control 6 at the proximal end of the catheter, in adesired direction for distal movement through the endovascular route andthen into and through the sinus cavernosus. More preferably, thecatheter has a conventional steering system which can actively bend thehollow tube of the catheter to a predetermined angle of no less than75°. Yet more preferably, the catheter has an exterior lumen within thehollow tube of the catheter and an interior lumen within the exteriorlumen. The exterior lumen contains a first steering mechanism, and theinterior lumen contains a second steering mechanism, that the first andsecond steering mechanisms being operable to actively bend the hollowtube to a predetermined angle of at least 80°, more preferably at least85°, yet more preferably at least 90°, when moving the distal end of thecatheter along the endovascular route. Such a catheter steeringmechanism is described, for instance, in U.S. Pat. No. 8,152,756 B2,US8715226B2 and US20050203413A1.

Also preferably, the exterior of the distal end of the catheter 1 of thesystem, adjacent to, and proximal of, the inflatable annular collar,also has a stabilizing device 28, shown in FIG. 19 , to secure theposition of the distal end of the catheter within the perforation in themedial wall of the sinus cavernosus, without occluding the perforation.Preferably, the stabilizing device 28 comprises an inflatable tripod 29,provided circumferentially about the exterior of the catheter and havinginflatable, radially extendable legs 30. Preferably, the stabilizingdevice 28 is connected to a source of air pressure (not shown), via amicrocannula 5 or 15 or via the hollow tube of the catheter, which caninflate the legs 30 of the device.

Also preferably, distal portions of each electrode or microcannula 5 or15 of the catheter 1 of the system have a form memory and thus can forma three-dimensional shape, such as a circle, oval or helix, within orabout/around the pituitary gland, preferably when triggered by remotecontrol. Still more preferably, distal portions of each electrode ormicrocannula, when inserted in the pituitary gland, have a coil shapewithin the pituitary gland.

Also preferably, a distal part of the catheter 1 of the system,particularly its hollow tube, has a conventional peel-away configuration(not shown), so that the catheter can be removed from a mammalianpatient after it has been used to insert an electrode or microcannula 5or 15 in the patient, so that the electrode or microcannula remainsintact and properly positioned in the patient. A suitable peel-awayconfiguration includes, for instance, those described in U.S. Pat. No.7,697,996B2.

Also preferably, the distal end of the catheter 1 of the system,containing one or more electrodes and/or one or more microcannulas 5 or15, is moved through the endovascular route from the vena jugularis ofthe mammalian patient, then to the inferior or superior petrosal sinusof the mammal, and then to the sinus cavernosus of the mammal, where asshown in FIG. 14 are the superior ophthalmic vein 19, inferiorophthalmic vein 20, Basilar plexus 21, inferior petrosal sinus 22,jugular vein 23, endovascular pituitary electrode 24, superior petrosalsinus 25, cavernous sinus 26 and circular venous plexus 27. Morepreferably, the distal end of the catheter is moved through theendovascular route from the ileac vein or femoral vein in a groin of themammal where the catheter has been inserted in the mammal. The distalend of an electrode or microcannula is then moved distally out of thecatheter, through the opening in the distal end of the catheter, andthrough the medial wall of the sinus cavernosus and is then insertedsubdurally into the pituitary gland 16 as shown in FIGS. 15 and 20 orpositioned epidurally of the pituitary gland as shown in FIG. 20 . Inthis regard, FIG. 20 particularly shows the trajectory of an electrode24 being either epidurally placed adjacent a surface of the pituitarygland 16 (at 31) or subdurally inserted into the surface of thepituitary gland 16 (at 32). The distal end of the subdurally placedelectrode or microcannula 5 or 15 can then be moved through thepituitary gland, then steered to move vertically and then inserted intothe pituitary stalk as shown in FIG. 16 . The distal end of theelectrode or microcannula can then be steered further vertically, thenpassed through the pituitary stalk 25 and then inserted into the core ofthe hypothalamus as shown in FIG. 17 . In this regard:

-   -   the catheter 1 can be pressed against the medial wall 11 of the        cavernous sinus as shown in FIG. 4 ; thereby, the cushion 8 is        pressed against the surface of the medial wall 11 of the sinus        cavernosus; the collar 10 can then be inflated as shown in FIGS.        5 and 6 to thereby seal off    -   the space around the distal end of the catheter; inflation and        deflation of the collar 10 can be done through a microcannula 5        or 15 or directly through the elongated hollow tube of the        catheter;    -   to allow full contact of the cushion 8 at the distal end of the        catheter with the medial wall 11 of the sinus cavernosus, the        pressure in the sealed space 12 can then be reduced as shown in        FIG. 7 by applying suction through a microcannula or through the        catheter; thereby, the medial wall 11 of the cavernous sinus is        pulled against the cushion 8 to provide full contact between the        two;    -   the medial wall of the cavernous sinus can then be perforated        with the sharp pointed tip 14 of the push wire 13 shown in FIGS.        8 and 9 ; in this regard, the tip 14 is preferably shallow,        e.g., only 1 mm long, so if the wall of the carotid artery is        accidently touched, the tip will not cause full thickness injury        of the carotid wall.    -   a pituitary electrode or microcannula 5 or 15 can then be        inserted, via the catheter into the pituitary gland 16 as shown        in FIGS. 10 and 11 for subdural treatment of the pituitary gland        or alternatively under or around the pituitary gland for        epidural treatment of the pituitary gland as shown in FIG. 20 .        Because the pressure in the sealed space 12 has been reduced,        the medial wall 11 of the cavernous sinus continues to adhere to        the cushion 8 at the distal end of the catheter;    -   when the pressure in the sealed space 12 is subsequently allowed        to normalize, the medial wall 11 of the cavernous sinus takes        its normal anatomical position, which allows some space between        it and the cushion 8; therefore, the sealed space 12 can then be        filled with an anchoring foam 17, supplied by an additional        microcannula 5 or 15, as shown in FIG. 13 or directly through        the elongated hollow tube of the catheter to form a cast of the        sealed space 12; the anchoring foam may then also seep through        the perforation of the medial wall 11 of the cavernous sinus 17;    -   the collar 10 can be deflated and the catheter 1 can be pulled        away from the medial wall 11 of the cavernous sinus, leaving the        electrode/microcannula 5 or 15 fixed in place by the anchoring        foam 17 and safely inserted into/around/under the pituitary        gland 16; the anchoring foam 17 effectively sealing the medial        wall of the cavernous sinus, preventing venous blood of the        cavernous sinus to seep in the space between medial wall 11 and        pituitary gland 16; and then    -   a stabilizing device 28 as shown in FIG. 19 , on the exterior of        the distal end of the catheter 1, can be used to secure the        position of the distal end of the catheter within the        perforation in the medial wall of the sinus cavernosus, without        occluding the perforation; preferably, the stabilizing device 28        includes an inflatable tripod 29, provided circumferentially        about the exterior of the catheter and having inflatable,        radially extendable legs 30.

The catheter 1 of this invention can provide electrical pulses and/ortherapeutic or diagnostic liquids directly to a pituitary gland of amammal or to a pituitary stalk or to a hypothalamus of the mammal viathe pituitary gland. The catheter contains one or more, conventionalaction members, a distal end of each of which can be moved in aconventional manner distally within the catheter through one or moreblood vessels of the mammal and then via a sinus cavernosus of themammal to a medial wall of the cavernous sinus. The catheter features:

-   -   an action member that is a push wire, a distal end of which has        a tip with a sharp, preferably pointed, element that can be        projected distally from an opening in the distal end of the        catheter to form a perforation in the medial wall of the        cavernous sinus, through which perforation the distal end of one        or more other action members, preferably one or more electrodes        and/or microcannulas, can be moved distally through the        cavernous sinus and the one or more other action members can        then be inserted in the pituitary gland from the distal end of        the catheter.

Preferably a distal-most part of the catheter includes a malleablecushion to allow good contact of the distal-most part with the surfaceof the medial wall of the sinus cavernosus. Also preferably, theexterior of the distal end of the catheter, adjacent to, and proximal,of the cushion contains an annular collar that can be inflated, so thatdistal surfaces of the collar are projected distally from the distal endof the catheter around the perforation in the medial wall of thecavernous sinus to close a space around the opening in the distal end ofthe catheter between the distal end of the catheter and the perforation,preferably before the tip of the push wire is projected distally fromthe opening in the distal end of the catheter to form the perforation inthe medial wall of the cavernous sinus. Also preferably, the exterior ofthe distal end of the catheter, preferably between the collar and thecushion, is provided with a ring that contains a radiopaque marking thatcan be recognized by X-ray, fluoroscopy, angiogram, MRI or a CT-scan.Also preferably, the distal end of the catheter can be pivoted orsteered in a desired direction, preferably by remote control, forcontrolling its distal movement through the endovascular route and theninto and through the sinus cavernosus.

The method of this invention provides electrical pulses and/ortherapeutic or diagnostic liquids directly to a pituitary gland of amammal or to a pituitary stalk or to a hypothalamus of the mammal viathe pituitary gland, comprising the steps of: moving a distal end of acatheter that contains one or more action members, preferably,preferably one or more electrodes and/or microcannulas, a distal end ofeach of which is movable distally within the catheter, through anendovascular route of the mammal route from the vena jugularis of themammal, to the inferior or superior petrosal sinus of the mammal, andthen to the sinus cavernosus of the mammal; and then forming aperforation in the medial wall of the cavernous sinus to the pituitarygland; and then moving the distal end of each of the one or more actionmembers distally from the catheter through an opening in the distal endof the catheter and then through the perforation in the medial wall ofthe sinus cavernosus, to the pituitary gland, preferably when the distalend of the catheter is adjacent the medial wall of the sinus cavernosus.

Preferably, the distal end of the catheter moves via one or more bloodvessels of an endovascular route from the ileac vein or femoral vein ina groin or the cephalic vein in the arm of the mammal where the catheteris inserted in the mammal.

With this system, its catheter and its method, one or more electrodes 5or 15 can be connected to a subcutaneous pulse generator and/or one ormore microcannulas 5 or 15 can be connected to a source of a therapeuticliquid, such as a pump and reservoir for regulatory hormones orproteins, RNAs, stem cells, cells that produce therapeutic substances,viruses, cells that can modify native pituitary gland cells andpharmaceutical compositions/drugs, and each electrode and/ormicrocannula can be implanted more safely in the pituitary gland, thepituitary stalk or the hypothalamus of a mammal patient for temporary orpermanent stimulation thereof. In this regard, endovascular access tothe basic core of the brain in accordance with this invention is simplerthan via the cerebral cortex and safer and easier than via the sinussphenoidalis. By treating the pituitary gland in this way withelectrical pulses and/or therapeutic liquids, it is believed that:pituitary functions could be stimulated or inhibited, as desired, andproblems of infertility, epilepsy, morbid obesity, and type II diabetescould be treated; and symptoms and diseases of the pituitary gland(e.g., Cushing's disease or Growth Hormone deficiency), as well asgeneral disorders (type II diabetes, adipositis and infertility) inwhich the pituitary gland is involved, could be treated.

In particular, the distal end of each of the one or more electrodes 5 or15 can be used to electrically stimulate the anterior and intermediatelobe of the pituitary gland to produce and secrete ACTH and/or MSH. Thedistal end of each electrode can also be used to electrically stimulatethe posterior lobe of the pituitary gland and thereby stimulate themagnocellular nuclei (i.e., the supraoptic and paraventricular nuclei)of the anterior hypothalamus through axons that descend through thepituitary stalk to the posterior lobe of the pituitary gland. Thepresent invention also relates to a method for spatial and temporalelectrically interfacing with an organ, preferably brain tissue, morepreferably the pituitary gland, the method comprising the steps of:providing an electrode array according to the invention, andelectrically contacting at least a portion of the plurality ofelectrodes with the tissue by conformally contacting a surface of thetissue with the electrode array; and spatio-temporally interfacing thebrain tissue with the conformable device to monitor or actuate aspatio-temporal profile over the surface of the brain tissue inelectrical contact with the plurality of electrodes; and actuatingelectrical activity over the brain surface by applying an electricpotential of a plurality of individual brain surface locations beneatheach electrode of the array of electrodes at a plurality of differentlocations and/or time points; and/or optionally, monitoring thespatio-temporal electrical brain profile with the device in conformaland electrical contact with a brain surface of a subject, wherein themonitoring comprises detecting an electric potential of a plurality ofindividual brain surface locations beneath each electrode of the arrayof electrodes at a plurality of different time points.

Moreover, electrical activity of a patient's pituitary cells andpituitary functions of a patient can be continuously measured andcontrolled via an electrode implanted in the pituitary gland andconnected to a controller implanted subcutaneously in the patient.Likewise, the pituitary stalk or the hypothalamus could be treated withelectrical pulses and/or therapeutic liquids or their functions could becontinuously measured and controlled. Moreover, a catheter can beprovided having an electrical stimulating device at its distal end whichcan be used for: i) identification of cranial nerves, particularly theabducens nerve; this can be done by EMG (electrode near or in the eye),or the patient indicating symptoms (diplopia); and ii) identifying thecarotid artery, for instance by measuring temperature, oxygenation,flow, pulsations or by echo doppler.

The present invention also relates to a method of alleviating anendocrinological condition in a patient suffering therefrom, the methodcomprising the steps of:

-   -   placing an electrode in electrical contact with the pituitary        gland;    -   detecting a bodily activity or a physiological change (e.g.,        temperature or heart rate) associated with the endocrinological        condition; and    -   activating the electrode to initiate application of an        electrical signal to the pituitary gland, or adjusting        application of an electrical signal to the pituitary gland in        response to alleviate the patient's endocrinological disorder.        In this regard, electrical stimulation of the pituitary gland by        the electrode can be used to treat the following indications:

Pituitary Gland Treatment Indication Anterior lobe Decrease ACTHProduction M. Cushing Anterior lobe/ Increase ACTH Production Secondaryadrenal intermediate insufficiency lobe Increase ACTH ProductionPituitary insufficiency Increase ACTH/alfa MSH Auto immune disordersProduction Modification ACTH Depression production Decrease PRLProduction Prolactinoma Modification FSH/LH Poly Cystic Ovary ProductionSyndrome Posterior lobe Increase Oxytocin Production Severe oncologicalpain Increase Oxytocin Anxiety disorders and Production PTSD

Preferably, the present invention also relates to a method for theintra-pituitary gland administration of a pharmacologically active agentinducing production of steroidal hormones in the adrenal glands of amammalian patient, the method comprising transferring into/around thepituitary gland a pharmaceutical preparation comprising an effectiveconcentration of the pharmacologically active component through amicrocannula as disclosed herein above. Preferably the active agentcomprises a corticotropin-releasing hormone (CRH) or analogue thereof,or any other suitable agent including peptides and/or oligonucleotides.

The present invention also relates to a system and method in which adistal end of an electrode array is implanted, preferably permanently,in an organ, preferably brain tissue, such as a pituitary gland, of amammalian patient for intermittent electrical stimulation thereof and aproximal end of the electrode is provided with a connection plug, adistal end of which can be attached to a bone adjacent the organ, suchan anterior wall of the sphenoid sinus/vomer, and a proximal end ofwhich can be reversibly connected electrically to a wire that isconnected electrically to a source of electrical stimulation for theorgan.

Preferably the electrode array is provided for interfacing with theorgan tissue in situ, the electrode array comprising: a. a deformablearray of electrodes comprising a plurality of electrodes in electricalcommunication with a plurality of deformable electrical interconnectsand a connector line; wherein the deformable array of electrodesprovides a net bending stiffness of the array low enough that the deviceis capable of establishing conformal contact with the tissue in situ;and b. a connection plug provided at the proximal end of the connectorline of the electrode array provided with a distal end of which can beattached to a bone adjacent the organ, such an anterior wall of thesphenoid sinus/vomer, and a proximal end of which can be reversiblyconnected electrically to a wire that is connected electrically to asource of electrical stimulation for the organ.

Preferably, the method according to the invention comprises the stepsof:

-   -   a. providing an electrode array as set out above, and i.        electrically contacting at least a portion of the plurality of        electrodes with the tissue by conformally contacting a surface        of the tissue with the electrode array; and ii.        spatio-temporally interfacing the brain tissue with the        conformable device to monitor or actuate a spatio-temporal        profile over the surface of the brain tissue in electrical        contact with the plurality of electrodes; and iii. actuating        electrical activity over the brain surface by applying an        electric potential of a plurality of individual brain surface        locations beneath each electrode of the array of electrodes at a        plurality of different locations and/or time points; and iv.        optionally monitoring the spatio-temporal electrical brain        profile with the device in conformal and electrical contact with        a brain surface of a subject, wherein the monitoring comprises        detecting an electric potential of a plurality of individual        brain surface locations beneath each electrode of the array of        electrodes at a plurality of different time points.

Preferably, the stimulation and/or monitoring comprises treating and/ormonitoring a patient suffering from an endocrinological medicalcondition. More preperably, the endocrinological medical conditioncomprises a problem related to the components of the endocrine system,such as the adrenal glands, pituitary gland, and hypothalamus, includinghypoglycemia, diabetes type I and II, obesity, hyperthyroidism,hypothyroidism, amenorrhea, dysmenorrhea, infertility, impotence,anorgasmia, delayed orgasm, perimenstrual syndrome,hypercholesterolemia, hypertriglycridinemia, Cushing's disease,Addison's disease, Addison's crisis, malabsorption syndrome,dysautonomia, epilepsy, chronic fatigue syndrome, fatigue, heatexhaustion, cold extremities, hot flashes, vasomotor instability,Raynaud's syndrome, hormonal disorders, metabolic disorders such asgout, disorders of metabolism and metabolic storage diseases where thereis an accumulation of abnormal amounts of various substances such asglycogen in glycogen storage diseases, iron in hemochromatosis or copperin Wilson's disease, auto-immune disorders, sleep disorders anddisruptions in the circadian rhythm. In particular the present inventionrelates to the treatment of Adison's disease and Adison's crisis, aswell as pain, pain perception, post-traumatic stress disorder,depression and anxiety.

What is claimed herein is:
 1. A system for providing electrical pulsesand/or therapeutic or diagnostic liquids directly to a pituitary glandof a mammalian patient or to a pituitary stalk, a hypothalamus, or otherbrain area of a mammalian patient via the pituitary gland; the systembeing movable through a catheter having a distal end comprising anopening, the catheter configured to be movable distally through bloodvessels of an endovascular route of the mammalian patient and then intoand through a sinus cavernosus of the mammalian patient, the systemcomprising: a (micro)electrode and/or a microcannula, a distal end ofwhich is configured to be movable distally within the catheter throughthe endovascular route, and then into and through the sinus cavernosus,and then distally out of the catheter through an opening in the distalend of the catheter, and then through a perforation in a medial wall ofthe sinus cavernosus to the pituitary gland, and then to and into oraround the pituitary gland; wherein the system is capable of activelybending to a predetermined angle of from 30° to 120° when moving alongthe endovascular route in the catheter.
 2. The system of to claim 1,wherein the catheter is provided for, and operable to move via theendovascular route from the ileac vein or femoral vein in a groin or thecephalic vein in the arm of the patient wherein the system furthercomprises at least two action members and/or steering members disposedin an exterior lumen, to actively bend or pivot the catheter to apredetermined angle of no less than 75°.
 3. The system of to claim 1,wherein the catheter further comprises: at least a first annular wallcomponent; at least a second annular wall component; and at least oneof: a) an annular lumen disposed between the first annular wallcomponent and the second annular wall component; and b) one or moreworking channels incorporated into the first annular wall componentand/or second annular wall component of the catheter, and at least aninterior lumen disposed inside the interior of the first annular wallcomponent and/or second annular wall component.
 4. The system of claim3, further comprising at least a secondary catheter for accessing thepituitary stalk, the secondary catheter being: located inside theprimary catheter; provided to be operable to project distally from thefirst catheter; and provided and operable for actively bending orpivoting at a predetermined angle of no less than 75°.
 5. The system ofclaim 3, wherein the first annular wall component and/or second annularwall component comprises at least one action member and/or steeringmember.
 6. The system according to claim 1, wherein at least one of theaction members is a push wire having a distal end that is disposed toand operable to move: distally within the catheter, through theendovascular route and then into and through the sinus cavernosus; andthen distally out of the catheter through the opening in the distal endof the catheter and then through the perforation in the medial wall ofthe sinus cavernosus.
 7. The system of claim 1, wherein the catheterfurther comprises a tip containing a sharp element that can be projecteddistally from the opening in the distal end of the catheter to form theperforation in the medial wall of the cavernous sinus.
 8. The system ofclaim 1, wherein a distal-most part of the catheter further comprises amalleable cushion to allow good contact of the distal-most part with thesurface of the medial wall of the sinus cavernosus; wherein the exteriorof the distal end of the catheter, adjacent to, and proximal of, themalleable cushion, comprises an annular collar that can be inflated orotherwise deployed, so that distal surfaces of the annular collar areprojected distally from the distal end of the catheter, enclosing avolume around the distal end of the catheter, around the perforation inthe medial wall of the cavernous sinus to close a space around theopening in the distal end of the catheter between the distal end of thecatheter and the perforation.
 9. The system of claim 2, wherein theaction member comprises at least a first guide wire for pivoting orsteering the distal end of the catheter in a desired direction, forcontrolling its distal movement through the endovascular route and theninto and through the sinus cavernosus.
 10. The system of claim 1,wherein an exterior of a distal part of the catheter and/or themicrocannula, comprises a radiopaque ring that can be recognized byX-ray, fluoroscopy, angiogram, MRI, or a CT-scan; and/or wherein adistal part of the catheter comprises an electromagnetic localizer whichcomprises a transmitter and receiver coil array, permitting it totransmit electromagnetic signals and receive electromagnetic energy froma transmitter coil array.
 11. The system of claim 8, wherein an exteriorof the distal end of the catheter, adjacent to, and proximal of, theannular collar, also comprises a stabilizing device comprising aninflatable tripod and provided circumferentially about an exterior ofthe catheter and comprising inflatable, radially extendable legs. 12.The system of claim 1, wherein a distal part of the catheter has apeel-away configuration, so that the catheter can be removed from thepatient in such a way that the electrode or microcannula remains intactand in place.
 13. The system of claim 1, wherein the system furthercomprises an electrode or electrode array, the distal end of which hasone or more contact points for electrical stimulation of endocrinetissue of the pituitary gland, the pituitary stalk, or the hypothalamus;and/or the system comprises a microcannula, the distal end of which hasone or more central hollow channels, each central hollow channelcomprising one or more side openings, through which small volumes of afluid or gel can flow into the pituitary gland, the pituitary stalk, orthe hypothalamus, preferably with side openings that can be opened andclosed by a remote control.
 14. The system of claim 13, wherein thedistal end of the electrode is adapted to: electrically stimulate thepituitary gland to produce and secrete adrenocorticotropic hormone(ACTH) and/or alpha-melanocyte stimulating hormone (MSH); and/orelectrically stimulate the pituitary gland to stimulate themagnocellular nuclei of the anterior hypothalamus through axons thatdescend through the pituitary stalk to the pituitary gland.
 15. Thesystem of claim 13, wherein a distal portion of the electrode orelectrode array and/or microcannula has a shape memory and thus can forma three-dimensional shape, within or about the pituitary gland.
 16. Thesystem of claim 15, wherein the electrode array is provided forinterfacing with an organ tissue in situ, the electrode arraycomprising: a) a deformable array of electrodes comprising a pluralityof electrodes in electrical communication with a plurality of deformableelectrical interconnects and a connector line; wherein the deformablearray of electrodes provides a net bending stiffness of the electrodearray low enough that the system is capable of establishing conformalcontact with the tissue in situ; and b) a connection plug at a proximalend of the connector line of the electrode array, the connection plugcomprising: a distal end which can be attached to a bone adjacent to theorgan tissue, including but not limited to an anterior wall of thesphenoid sinus and/or vomer, and a proximal end which can be reversiblyconnected electrically to a wire that is connected electrically to asource of electrical stimulation for the organ tissue.
 17. The system ofclaim 3, wherein the first annular wall component and/or second annularwall component is removable while leaving the microcannula and/or theelectrode or electrode array in place, and optionally, furthercomprising an optionally subcutaneously provided reservoir and/orcontrol or pump unit for controlling and providing electrical pulsesand/or therapeutic or diagnostic liquids directly to a pituitary glandvia the microcannula or electrode, and/or measuring of currents in theelectrode or electrode array.
 18. A method for providing electricalpulses and/or therapeutic or diagnostic liquids directly to a pituitarygland of a mammalian patient or to a pituitary stalk or to ahypothalamus or other basal ganglia of the brain of the mammalianpatient via the pituitary gland, comprising the steps of: moving thedistal end of a catheter of a system according to claim 1 through anendovascular route of the mammalian patient from a vena jugularis of themammalian patient, to an inferior or superior petrosal sinus of themammalian patient, and then to a sinus cavernosus of the mammalianpatient; perforating a medial wall of the cavernous sinus to thepituitary gland; moving the distal end of the electrode or microcannulaor both distally from the catheter, through the opening in the distalend of the catheter and through the perforated medial wall of the sinuscavernosus, to the pituitary gland; and removing the annular wallsection of the catheter after leaving the electrode and/or microcannulain place.
 19. A method of alleviating an endocrinological medicalcondition in a mammalian patient suffering therefrom, the methodcomprising the steps of: (i) placing an electrode or electrode array inelectrical contact with the pituitary gland of the mammalian patientusing a system according to claim 1; (ii) detecting an activityassociated with, or of relevance to, the endocrinological medicalcondition; and (iii) activating the electrode or electrode array toinitiate application of an electrical signal to the pituitary gland, oradjusting application of an electrical signal to the pituitary gland toalleviate, repair, or prevent worsening of the patient'sendocrinological medical condition; wherein the endocrinological medicalcondition comprises a problem related to the components of the endocrinesystem, including but not limited to the adrenal glands, pituitarygland, and hypothalamus, including hypoglycemia, diabetes type I and II,obesity, hyperthyroidism, hypothyroidism, amenorrhea, dysmenorrhea,infertility, impotence, anorgasmia, delayed orgasm, perimenstrualsyndrome, hypercholesterolemia, hypertriglycridinemia, Cushing'sdisease, Addison's disease, Addison's crisis, malabsorption syndrome,dysautonomia, epilepsy, chronic fatigue syndrome, fatigue, heatexhaustion, cold extremities, hot flashes, vasomotor instability,Raynaud's syndrome, hormonal disorders, metabolic disorders such asgout, disorders of metabolism and metabolic storage diseases where thereis an accumulation of abnormal amounts of various substances such asglycogen in glycogen storage diseases, iron in hemochromatosis or copperin Wilson's disease, auto-immune disorders, sleep disorders anddisruptions in the circadian rhythm. In particular the present inventionrelates to the treatment of Adison's disease and Adison's crisis, aswell as pain, pain perception, post-traumatic stress disorder,depression and anxiety.
 20. A method for the intra-pituitary glandadministration of a pharmacologically active agent inducing orinhibiting production of steroidal hormones in the adrenal glands of amammalian patient through change of the pituitary gland function,including but not limited to wherein the active agent comprises acorticotropin-releasing hormone (CRH) or analogue thereof, orcombinations of CRH with other pharmacologically active components likevasopressin, the method comprising: i)a) transferring into the pituitarygland a pharmaceutical preparation comprising an effective concentrationof the pharmacologically active agent through the microcannula of thecatheter of the system according to claim 1; and/or i)b) electricallycontacting at least a portion of the plurality of electrodes with thetissue by conformally contacting a surface of the tissue with theelectrode array of a system according to claim 1; ii) spatially andtemporally interfacing a brain tissue with the conformable device tomonitor or actuate a spatio-temporal profile over the surface of thebrain tissue in electrical contact with the plurality of electrodes; andiii) actuating electrical activity over the surface of the brain tissueby applying an electric potential to a plurality of individual brainsurface locations, each beneath an electrode of the plurality ofelectrodes at a plurality of different locations and/or time points. 21.The method of claim 20, further comprising monitoring thespatio-temporal electrical brain profile with the device in conformaland electrical contact with a brain surface of the subject, wherein themonitoring comprises detecting an electric potential of a plurality ofindividual brain surface locations beneath each electrode of the arrayof electrodes at a plurality of different time points.